Design, synthesis, biological evaluation and molecular dynamics simulation studies of (R)-5-methylthiazolidin-4-One derivatives as megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) inhibitors for the treatment of type 2 diabetes

Abstract

PTP-MEG2 plays a significant role in insulin production and is able to enhance insulin signaling and improve insulin sensitivity. So, PTP-MEG2 inhibitors are closely associated with type 2 diabetes therapy. A series of novel (R)-5-methylthiazolidin-4-one derivatives were designed and synthesized, and their PTP-MEG2 inhibitory activities (IC50) were determined. Among the desired compounds, 1h shares the highest inhibitory activity (IC50 = 1.34 μM) against PTP-MEG2. Additionally, various post-dynamic analyses confirmed that when compound 1h bound to the PTP-MEG2, the protein conformations became unstable and the function of the pTyr recognition loop (Asn331-Cys338) would be disturbed. And thus, the ideal conformations needed for the catalytic activity was difficult to be maintained. In brief, these might be how the compound 1h worked. Furthermore, we also found that the key residues Arg332 would play a critical role in disturbing the residue interactions.AbbreviationsDCCMdynamic cross-correlation mappingDMFN,N-dimethylformamideDSSPdefinition of secondary structure of proteinsFOXOforkhead transcription factorsMDmolecular dynamicsPCAprincipal component analysisPDBprotein data bankPTKsprotein tyrosine kinasesPTPsprotein tyrosine phosphatasesPTP-MEG2megakaryocyte protein tyrosine phosphatase 2RINresidue interaction networkRINGResidue Interaction Network GeneratorRMSDroot means square deviationRMSFroot mean square fluctuationCommunicated by Ramaswamy H. Sarma